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Updated: May 17, 2026
Tumor Treating Field Therapy in Combination with Bevacizumab for the Treatment of Recurrent Glioblastoma
Published on: October 27, 2014
Mibefradil, a novel therapy for glioblastoma multiforme: cell cycle synchronization and interlaced therapy in a
Stephen T Keir1, Henry S Friedman, David A Reardon
1Duke University Medical Center, Durham, NC, USA. stephen.keir@duke.edu
Abstract:
Glioblastoma multiforme (GBM) is a devastating disease with a dismal prognosis and a very limited response to treatment. The current standard of care for GBM usually consists of surgery, radiation and chemotherapy with the alkylating agent temozolomide, although resistance to this drug is common. The predominant mechanism of action of temozolomide is methylation of guanine residues although this can be reversed by methylguanine methyltransferase (MGMT) as well as other DNA repair systems. The presence of methylguanine causes abortive DNA synthesis with subsequent apoptosis. This suggests that the closer a particular cell is to S phase when it is exposed to temozolomide the more likely it is to die since repair enzymes will have had less time to reverse the damage. T type calcium channel inhibitors can stop the entry of extracellular calcium that is necessary for transit past the G1/S boundary. As a result, T type calcium channel blockers can slow the growth of cancer cells, but do not generally kill them. Though slowing the growth of cancer cells is important in its own right, it also provides a therapeutic strategy in which a T type channel blocker is administered then withdrawn followed by the administration of temozolomide. We show here that imposing this cell cycle restriction increases the efficacy of subsequently administered temozolomide in immunodeficient mice bearing various human GBM xenograft lines. We also present data that MGMT expressing GBM tumors, which are temozolomide resistant, may be rendered more sensitive by this strategy.
Insights
Combining T type calcium channel blockers with temozolomide chemotherapy enhances glioblastoma treatment. This novel strategy improves efficacy, even in temozolomide-resistant tumors expressing MGMT.
Area of Science:
- Oncology
- Cancer Biology
- Pharmacology
Background:
- Glioblastoma multiforme (GBM) presents a poor prognosis with limited treatment options.
- Temozolomide (TMZ) is a standard chemotherapy agent for GBM, but resistance is common.
- Temozolomide resistance can be mediated by DNA repair enzymes like methylguanine methyltransferase (MGMT).
Purpose of the Study:
- To investigate a novel therapeutic strategy combining T type calcium channel blockers with temozolomide for GBM treatment.
- To determine if cell cycle restriction can enhance the efficacy of temozolomide.
- To assess the effectiveness of this strategy in temozolomide-resistant GBM models.
Main Methods:
- Utilized immunodeficient mice bearing human GBM xenograft lines.
- Administered T type calcium channel blockers to induce cell cycle arrest.
- Followed by withdrawal of T type calcium channel blockers and administration of temozolomide.
- Evaluated tumor response and efficacy in xenograft models, including those expressing MGMT.
Main Results:
- Cell cycle restriction using T type calcium channel blockers significantly increased the efficacy of subsequent temozolomide treatment.
- This combined approach demonstrated enhanced effectiveness in various human GBM xenograft lines.
- MGMT-expressing GBM tumors, typically resistant to temozolomide, showed increased sensitivity to the combined therapy.
Conclusions:
- Combining T type calcium channel blockers with temozolomide represents a promising therapeutic strategy for glioblastoma.
- This approach can overcome temozolomide resistance, particularly in tumors with high MGMT expression.
- Cell cycle modulation offers a viable method to enhance chemotherapy effectiveness in GBM treatment.
